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  • 1
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    Unmutated IGHV1-69/D3-16/J3 Stereotyped HCDR3 Rearrangements (Subset 6) Are Associated with Indolent Disease Course and Have Outcome Independent of Mutational Status In Early Stage CLL (Rai 0)
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1371-1371
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1371-1371
    Abstract: Abstract 1371 Background: IGHV1-69 gene identifies the most frequent IGHV gene in chronic lymphocytic leukemia (CLL) and identifies the paradigm of unmutated CLL (U-CLL), being used in roughly 1/3 U-CLL. It is often rearranged to form subsets of stereotyped HCDR3 patterns, likely selected and transformed from the natural naïve B-cell repertoire (Blood. 2010; 115:71-7). Being unmutated, IGHV1-69 CLL are hypothetically expected to have competent tumor B-cell receptors (BCR) and to progress more rapidly. However, it has not been investigated if progression occurs similarly in all the subsets. Aims: we aimed to investigate the prognostic significance of mutational status and of stereotypic B-cell receptors in IGHV1-69+ CLL. Methods: Nucleotide sequences of the tumor IGHV1-69/D/J rearrangement, clinical and molecular prognostic parameters at diagnosis and clinical status at follow-up of 294 IGHV1-69+ CLL patients were obtained from 22 hematological Institutions in Italy. CLL B-cell derived IGHV1-69 rearrangements were scanned for HCDR3 stereotypic patterns and assigned to subsets according to the criteria by Murray et al (Blood. 2008; 111: 1524–1533). Enpoint of outcome was time to progression requiring first treatment according to NCI criteria (TTFT) in Rai stage 0 CLL. Results: Of 294 IGHV1-69+ CLL, 264 (89,8%) were unmutated, 168 (57,1%) were assigned to subsets, of which subsets 7 (n=23, 7,8%), 6 (17, 5,8%), 3 (13, 4,4%), 5 (10, 3,4%) and 9 (10, 3,4%) were the most frequent. CD38, ZAP70, normal or sole del13, +12, del11 and del17p scored positive in 109/264 (58,7%), 139/245 (56,7%), 128/248 (50,5%), 51/248 (20,6%), 43/248 (17,3%) and 34/248 (13,7%). CLLs were reclassified as 18 (6,1%) clinical MBL, 101 (34,4%) Rai 0, 155 (52,7%) Rai I-II and 20 (6,8%) Rai III-IV CLL. Subset 6 was also UM in 16/17 (94,1%) cases. Prevalence of CD38 (p 〈 .001), ZAP70 (p=.016), normal or sole del13 (p 〈 .001), +12 (p=.026), del11 (p=.011), and clinical high risk CLL (p=.025) were lower in IGHV1-69 M-CLL than in IGHV1-69 U-CLL. TTFT was significantly shorter in stage 0 IGHV1-69 U-CLL than in IGHV1-69 M-CLL (49 vs 144 months, p 〈 .001, while it was not different between CLL assigned or not to subsets (65 vs 55 months, p=.346). However, specific analysis of individual subsets revealed differential outcomes (p=.005). Among all, it emerged that subset 6 had a TTFT equivalent to IGHV1-69 M-CLL (p=.29) and significantly longer than stage 0 IGHV1-69 U-CLL (median not reached vs 48 months, p=.017). Conclusions: our analysis documents and confirms that unmutated status of IGHV, and not stereotypy, is a relevant prognosticator of outcome (TTFT) in CLL. In the IGHV1-69 CLL it exclude a role of IGHV gene use for CLL progression. However, the good prognosis of Rai 0 U-CLL assigned to subset 6 suggests a differential clinical benign course of this particular subset, irrelevant of unmutated status. One possibility is that the IGHV1-69/D3-16/J3 rearrangements of subset 6 produce a tumor-specific BCR with stereotypic HCDR3 patterns that are anergized by antigen while circulating in the peripheral blood in early stage (Rai 0) CLL. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1371.1371
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    13q14 Chromosome Deletion Size and Number of Deleted Cells Influence Prognosis In Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3578-3578
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3578-3578
    Abstract: Abstract 3578 Introduction: Chronic lymphocytic leukemia (CLL) patients bearing 13q14 deletion are known to experience a more favorable clinical course. Recent studies, focusing on patients with loss of 13q as the sole cytogenetic aberration at diagnosis (del13q-only cases), showed that the number of malignant cells carrying this genetic lesion correlates with a more aggressive clinical behavior. However, whether the size of the 13q deletion may also influence the clinical outcome remains to be elucidated. Patients and Methods: Probes for chromosome 13q (LSI-RB1, LSI-D13S319), 11q (LSI-ATM), 17p (LSI-p53) and chromosome 12 (CEP12) were utilized on nuclei collected at diagnosis from: i) a multi-institutional CLL cohort (342 del13q-only cases) and ii) a consecutive unselected single-institution cohort of 265 cases. RB1 deleted cases (delRB1) were defined as having at least 5% of deleted nuclei. Time to treatment (TTT) intervals, as well as Rai staging, IGHV mutational status, CD38 and ZAP70 expression, B2-microglobulin levels, all evaluated at diagnosis, were also available for all cases that entered the study. Genome wide DNA profile was performed in a pilot series of 90 CLL samples using Affymetrix GeneChip Human SNP6 arrays. Results: According to genome wide DNA analysis, delRB1 occurred in a proportion of del13q-only cases (36/90; 40%), always comprising the deleted region detected with the LSI-D13S319 probe (that covers the miR-15a/16-1 cluster and the DLEU2 gene) and characterized by a larger chromosome loss (median size 2.07 Mb vs. a median size of 0.86 Mb for the canonical del13S319). Maximally selected log-rank statistics identified the 70% of nuclei bearing del13S319 as the most appropriate cut-off value capable of separating del13q-only cases into two subgroups with different TTT distributions. Consistently, del13q-only cases with at least 70% of nuclei bearing del13S319 showed a significantly shorter TTT than del13q-only cases with less than 70% deleted nuclei (p=0.0001). Del13q-only cases were then divided in four subsets according to the percentage of nuclei bearing del13S319 with or without a concomitant delRB1: del13S319 〈 70% (group 1), 144 cases; del13S319 〈 70% + delRB1 (group 2), 95 cases; del13S319 〉 70% (group 3), 64 cases; del13S319 〉 70% + delRB1 (group 4), 39 cases. The median TTT of group 1 (not reached) was significantly longer than the median TTT of group 2 (92 months, p=0.012), group 3 (68 months, p 〈 0.0001), and group 4 (82 months, p=0.0025; see Fig. 1A). Multivariate Cox proportional hazard analyses selected the presence of delRB1 (p=0.029), along with the IGHV mutational status (p 〈 0.0001), as an independent negative prognosticator in the context of del13q-only cases with low/intermediate Rai risk (Rai stage of 0/I at diagnosis) and 〈 70% of del13S319. Cases belonging to the consecutive unselected single-institution CLL cohort were divided into subsets according to the classification proposed by Döhner et al (NEJM, 2000). Notably, the presence of del13S319 in 〈 70% of cells in the absence of delRB1 identified a patient subset with particularly stable and benign clinical course (group A in Fig. 1B, 48 cases; median TTT not reached). Conversely, patients characterized by del13S319 in 〈 70% of cells but with a larger deletion, as determined by concomitant delRB1 (group B, 24 cases), or del13S319 in 〉 70% of cells (with or without delRB1, group C, 25 cases) or a normal karyotype (group D, 75 cases) had shorter median TTT intervals (ranging from 105 to 129 months, p 〈 0.01 in all the comparisons). Finally, patients affected by CLL bearing trisomy 12 (group E, 48 cases) and del11q or del17p (group F, 45 cases) experienced the worst clinical courses (p 〈 0.0001). Conclusion: In the context of del13q-only cases, different clinical outcomes were associated to the percentage of 13q14 deleted cells, as well as to the size of the 13q14 deletion, as detected by the LSI-RB1 probe. Moreover, the presence of delRB1 emerged as a feature capable of refining the prognostic assessment in the context of CLL cases with 〈 70% del13S319. The underlying genetic mechanisms correlated with the different clinical outcomes and associated with the size of the 13q deletion are presently under investigation. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3578.3578
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Mutations of the SF3B1 splicing Factor in Chronic Lymphocytic Leukemia: Association with Progression and Fludarabine-Refractoriness
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 464-464
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 464-464
    Abstract: Abstract 464 Fludarabine-refractoriness of chronic lymphocytic leukemia (CLL) is due to TP53 disruption in ∼40% of refractory cases, but in a sizeable fraction of patients the molecular basis of this aggressive clinical phenotype remains unclear. Our initial findings from whole exome sequencing of fludarabine-refractory CLL led to the identification of recurrent mutations of SF3B1, a critical component of the cell spliceosome, prompting further investigations of these alterations in a large CLL panel. The study population comprised 3 clinical cohorts representative of: i) fludarabine-refractory CLL (n=59), including cases (n=11) subjected to whole exome sequencing; ii) newly diagnosed and previously untreated CLL (n=301); and iii) clonally related RS (n=33). Tumor samples were obtained: i) for fludarabine-refractory CLL, immediately before starting the treatment to which the patient eventually failed to respond; ii) for newly diagnosed and previously untreated CLL, at disease presentation. All RS studies were performed on RS diagnostic biopsies. Mutation analysis of SF3B1 was performed on genomic DNA by a combination of Sanger sequencing and targeted next generation sequencing. SF3B1 was altered in 10/59 (17%) fludarabine-refractory CLL by missense mutations (n=9) or in-frame deletions (n=1) clustering in the HEAT3, HEAT4 and HEAT5 repeats of the SF3B1 protein. Two sites that are highly conserved inter-species (codon 662 and codon 700) were recurrently mutated in 3 and 5 cases, respectively. SF3B1 mutations were monoallelic, and were predicted to be functionally significant according to the PolyPhen-2 algorithm. Mutations occurred irrespective of IGHV mutation status, CD38 expression and ZAP70 expression. At the time of fludarabine-refractoriness, SF3B1 mutations were enriched in cases harboring a normal FISH karyotype (p=.008) and distributed in a mutually exclusive fashion with TP53 disruption (mutual information I =0.0609; p=.046). By combining SF3B1 mutations with other genetic lesions enriched in chemorefractory cases (TP53 disruption, NOTCH1 mutations, ATM deletion), fludarabine-refractory CLL appeared to be characterized by multiple molecular alterations that, to some extent, are mutually exclusive. We then compared the prevalence of mutations observed at the time of fludarabine-refractoriness to that observed in other disease phases. At diagnosis, SF3B1 mutations were rare (17/301; 5%), and showed a crude association with short treatment free survival (p 〈 .001) and overall survival (p=.011). Remarkably, 5/17 (29%) CLL mutated at diagnosis were primary fludarabine-refractory patients. In CLL investigated at diagnosis, the hotspot distribution and molecular spectrum of SF3B1 mutations, as well as their mutual relationship with other genetic lesions, were similar to those observed in fludarabine-refractory CLL. SF3B1 mutations were restricted to 2/33 (6.0%) clonally-related RS. Across the different disease phases investigated, mutations were somatically acquired in all cases (n=18) for which germline DNA was available. These data document that mutations of SF3B1, a splicing factor that is a critical component of the spliceosome; i) recurrently associate with fludarabine-refractory CLL; ii) occur at a low rate at CLL presentation; iii) play a minor role in RS transformation, corroborating the notion that CLL histologic shift is molecularly distinct from chemorefractory progression without RS transformation. The identification of SF3B1 mutations points to the involvement of splicing regulation as a novel pathogenetic mechanism in CLL. The pathogenicity of SF3B1 mutations in CLL is strongly supported by clustering of these mutations in evolutionarily conserved hotspots localized within HEAT domains, which are tandemly arranged curlicue-like structures serving as flexible scaffolding on which other components can assemble. Also, the observation that SF3B1 regulates the alternative splicing program of genes controlling cell cycle progression and apoptosis points to a potential contribution of SF3B1 mutations in modulating tumor cell proliferation and survival. In addition to pathogenetic implications, SF3B1 mutations might also provide a therapeutic target for SF3B1 inhibitors, that are currently under pre-clinical development as anti-cancer drugs. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.464.464
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
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    A Molecular Model to Predict Durable Remission after First Line Fludarabine-Cyclophosphamide-Rituximab Treatment in Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3300-3300
    Abstract: Background. Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant advancement in the treatment of patients with chronic lymphocytic leukemia (CLL) and has the potential of inducing durable remissions of the disease. In the new scenario of targeted agents for CLL, there is an increasing interest in identifying patients who may gain the maximum benefit in terms of disease control by a single shot of FCR chemo-immunotherapy. Purpose. Here we aimed at identifying predictors of durable remission after first line FCR treatment. Methods. The study was based on 405 progressive and previously untreated CLL patients who consecutively received standard FCR (up to 6 cycles) as first line therapy in 19 hematologic centers between 2001 and 2010. According to an intention to treat approach, all patients who received at least one FCR cycle were registered in the study. This series was representative of a FCR treated CLL cohort with respect to baseline characteristics, including age (median: 61 years; 〉 65 years in 33% of patients), gender (male in 68% of patients), stage (progressive Binet A in 11% of patients; Binet B in 59%; Binet C in 30%) and number of FCR courses (median: 6; 〈 6 in 42% of patients). Most patients were evaluable for IGHV mutation status (unmutated in 192/296, 65%) and genomic aberrations at treatment requirement (17p deletion in 30/306, 9.8%; 11q deletion in 56/300, 19%; +12 in 70/298, 23%; 13q deletion in 108/301, 36%). Results. After a median follow-up of five years, 159 patients have progressed and 72 have died, accounting for a 5-year progression free survival (PFS) according to the IWCLL criteria of 47% (median: 58 months) and for a 5-year overall survival (OS) of 81% (median: not reached). When the demographic effects of age, gender and year of treatment were compensated, the 5-year and 10-year survival of the whole CLL cohort were 85% and 68%, respectively, of those expected in the matched normal general population (p 〈 0.001). By multivariate analysis, unmutated IGHV genes, 11q deletion and 17p deletion maintained independent association with both PFS and OS, thus providing the rationale to utilize them in the development of a model to predict remission duration after FCR. By recursive partitioning analysis, 17p deletion was the most important variable in predicting PFS after FCR, followed by 11q deletion and IGHV mutation status (Fig. 1A). Based on the application of an amalgamation algorithm, cases harboring unmutated IGHV genes and 11q deletion were grouped into a single category because they showed an identical drop of the PFS curve (Fig. 1A). By this approach, three CLL subgroups were hierarchically classified. Clinical features and treatment indication were superimposable across the three risk groups. The low risk category comprised patients harboring mutated IGHV genes but neither 11q or 17p deletion, and accounted for 26% of all cases. Most of the low risk patients (67%) remained free of progression after FCR (Fig. 1B), and their hazard of relapse dropped to zero after 5 years of follow-up. Consistently, the PFS curve of low risk patients plateaued after 5-years from FCR (Fig 1B). The life expectancy of low risk patients (91% at 5 year) was superimposable to that observed in the matched normal general population (Fig. 1D), indicating that neither the disease, nor complications of its treatment affected survival in this favorable group of CLL. Conversely, patients belonging to the intermediate risk (IGHV unmutated and/or 11q deleted) and high risk (17p deleted) categories showed a constant increase of the hazard of progression over time and almost all were projected to relapse after FCR, although at a different rate: 10% per year of follow-up in the intermediate risk group and 17% per year of follow-up in the high risk group (Fig. 1B-C). The 5-year life expectancy of intermediate and high-risk patients was significantly impaired compared to that observed in the matched general population (85% and 60%, respectively) (Fig. 1D), indicating an excess of deaths related to the disease or treatment complications in these unfavorable groups of CLL. Conclusions. The combination of three biomarkers that are routinely tested at treatment allows to segregate a subgroup of CLL (IGHV mutated without 17p or 11q deletion) that may achieve a durable remission after first line FCR treatment and experience an expected survival similar to that of the general population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3300.3300
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
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    13q14 Deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia
    Wiley ; 2011
    In:  Genes, Chromosomes and Cancer Vol. 50, No. 8 ( 2011-08), p. 633-643
    Details
    In: Genes, Chromosomes and Cancer, Wiley, Vol. 50, No. 8 ( 2011-08), p. 633-643
    Type of Medium: Online Resource
    ISSN: 1045-2257
    URL: Issue
    URL: Article
    DOI: 10.1002/gcc.v50.8
    DOI: 10.1002/gcc.20885
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 1018988-9
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    SSG: 12
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  • 6
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    B-cell receptor, clinical course and prognosis in chronic lymphocytic leukaemia: the growing saga of the IGHV3 subgroup gene usage : Review
    Wiley ; 2011
    In:  British Journal of Haematology Vol. 153, No. 1 ( 2011-04), p. 3-14
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    In: British Journal of Haematology, Wiley, Vol. 153, No. 1 ( 2011-04), p. 3-14
    Type of Medium: Online Resource
    ISSN: 0007-1048
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2011.153.issue-1
    DOI: 10.1111/j.1365-2141.2010.08440.x
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    Language: English
    Publisher: Wiley
    Publication Date: 2011
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  • 7
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    NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukemia undergoing first-line treatment: correlation with biological parameters and response to treatment
    Informa UK Limited ; 2014
    In:  Leukemia & Lymphoma Vol. 55, No. 12 ( 2014-12), p. 2785-2792
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    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 55, No. 12 ( 2014-12), p. 2785-2792
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    URL: Article
    DOI: 10.3109/10428194.2014.898760
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2014
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  • 8
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    Minimal Residual Disease Evaluated As Bcl2/Igh Rearrangement After Conventional Treatment Does Significantly Impact On Progression-Free Survival of Patients Affected by Follicular Lymphoma: The Experience of the Ancillary Trial Conducted by the Fondazione Italiana Linfomi (FIL)
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3653-3653
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3653-3653
    Abstract: Abstract 3653 Background. The rearrangement Bcl2/IgH is detectable by PCR in more than half of patients with follicular lymphoma. Different authors reported on the long-term prognostic impact of the persistence of this rearrangement (minimal residual disease or MRD). In this study, we report about MRD significance in 534 patients randomized to receive 8 doses of Rituximab associated with 8 cycles of CVP, or 6 cycles of CHOP or FM, and no maintenance in the context of the Fondazione Italiana Linfomi (FIL) multicenter phase-III “FOLL05” trial (NCT00774826). Patients and methods. For qualitative PCR analysis, samples were centralized. Quantitative assays were performed by the 4 laboratories of the “FIL MRD NETWORK”. Qualitative and quantitative PCR were performed according to the Euro-MRD guidelines. Results. At baseline, 424 out of the 504 patients enrolled were assessed for Bcl2/IgH and 223 (52,6%) were Bcl2/IgH positive (molecular marker=MM). No significant differences were detected between cases with and without molecular assessment at the enrollment or after therapy, and those with positive or negative MM for the main clinical and prognostic features, and for treatment allocation. At the first time-point (within 6 weeks after the end of therapy), 153 of the 223 cases PCR-positive at enrollment were re-assessed: 110 (69,6%) achieved PCR negativity. MRD was not significantly correlated to clinical features or quality of clinical response. Three-year PFS was better for patients achieving PCR negativity at the sixth week than those retained MM (69% vs 50%), but this difference was not statistically significant. On the contrary, PFS was significantly conditioned by the PCR status at 12 and 24 months (87 and 66 cases evaluable), with 3-year PFS of 66% for cases PCR-negative versus 41% for those PCR-positive at 12 months (p=0.015, see Figure 1), and 84% vs 50% (p=0.014) at 24 months. Moreover, the probability of being PCR-negative by 24 months was significantly lower for cases receiving R-CVP (18% vs 41% in the R-CHOP and 41% in the R-FM, p=0.035). PCR-negativity resulted in better PFS both in CR and in PR patients (3-year PSF=72% for cases CR/PCR- vs 32% for those CR/PCR+ vs 62% for those PR/PCR- and 25% for patients in PR/PCR+; p=0.001). When PCR negativity in patients with or without complete response and PCR negativity by 12 months were considered in a multivariate analysis together with performance status, FLIPI, response, and age, the PCR negativity retained its favorable impact on PFS (HR=-1.2, 95% CI:0.32–0.19, p=0.001). Finally, in 105 cases tumor burden at the diagnosis was assessed by quantitative PCR. The median value was 3 × 10−3 copies; cases displaying values 〈 1 × 10−4 showed a clear advantage in terms of PFS (3-year PFS of 80% vs 59% for those with 〉 1 × 10−4 copies p=0.015). A significant MRD clearance was observed at the end of therapy: the mean value of Bcl2/IgH was 2 × 10−1 copies before therapy versus 5 × 10−3 at the first time-point. No differences in the entity of the MRD clearance were observed according to the arm of treatment. Conclusions. In conclusion, this study shows that R-CHOP and R-FM are more effective to clear MRD in follicular lymphoma compared to R-CVP. Moreover, the most prominent impact on PFS is exerted by the molecular status detected at least 6 months after the end of therapy. This observation is in line with the hypothesis of a quite slow, but long-term sustained, MRD clearance exerted by rituximab-based therapies. Finally, this study shows that patients with 〈 1 × 10−4 copies of Bcl2/IgH at diagnosis would have longer PFS, thus supporting the usefulness of a quantitative PCR monitoring at diagnosis. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3653.3653
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 9
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    Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness
    American Society of Hematology ; 2014
    In:  Blood Vol. 123, No. 15 ( 2014-04-10), p. 2378-2388
    Details
    In: Blood, American Society of Hematology, Vol. 123, No. 15 ( 2014-04-10), p. 2378-2388
    Abstract: The coding genome of fludarabine-refractory CLL patients is characterized by 16 mutations/case and 4 copy number aberrations per case on average. Fludarabine-refractory CLL cases are enriched in FAT1 mutations occurring in 10% of patients, suggesting a role in the refractoriness event.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2013-10-534271
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 10
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    NOTCH1, SF3B1 and BIRC3 Mutations in Chronic Lymphocytic Leukemia (CLL) Patients Requiring First-LINE Treatment: Correlation with Biological Parameters and Response to Treatment
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 1784-1784
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    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1784-1784
    Abstract: Abstract 1784 Introduction: The introduction of whole exome sequencing has allowed to unravel novel molecular lesions in CLL. NOTCH1, SF3B1 and BIRC3 mutations are detected, according to the phases of disease, in 4–12%, 5–17% and 4–24% of patients, respectively. In retrospective studies, their presence has been shown to correlate with overall survival (OS) and treatment-free interval shortening. Aims: To define the incidence, correlation with known prognostic factors and clinical impact of NOTCH1, SF3B1 and BIRC3 mutations in CLL patients undergoing first-line treatment. Methods: We evaluated 162 CLL patients enrolled in the GIMEMA LLC0405 protocol (n=80) for patients aged 〈 60 yrs and in the ML21445 protocol (n=82) for elderly patients (aged 〉 65 yrs or 60–65 if not eligible for fludarabine-based programs). In the GIMEMA LLC0405 protocol, patients were stratified into low and high-risk: patients with del17p or with del11q plus an unmutated IGHV status and/or CD38 positivity and/or ZAP70 positivity were considered as high-risk (HR) and underwent Fludarabine plus Campath, followed by stem cell transplantation procedures, whereas low-risk patients received Fludarabine and Cyclophosphamide. The MLL21445 protocol consisted of 8 cycles of Chlorambucil and 6 of Rituximab induction treatment. NOTCH1 (exon 34), SF3B1 (exons 14 and 15) and BIRC3 (exons 2–9, including splicing sites) were screened by Sanger sequencing on either genomic DNA (gDNA) or whole genome amplified DNA (WGA) collected at the time of treatment. These studies were not part of the clinical protocols. Results: NOTCH1 mutations were detected at the time of treatment in 18 cases (22%) enrolled in the LLC0405 study. There was a significant association with high-risk stratification (p=0.036), namely with an IGHV unmutated status (p=0.0035), CD38 (p=0.03), +12 (p=0.034) and, partly, ZAP-70 expression (p=0.059). While the overall response rate (ORR) did not differ between NOTCH1 mutated vs wild-type (WT) cases (82% vs 77%, respectively), the complete response (CR) rate was significantly lower in NOTCH1 mutated patients (43% for WT vs 17% for NOTCH1 mutated cases; p=0.05). So far, no significant difference between mutated and WT patients has emerged in terms of OS and progression-free survival (PFS); this may be contributed by the fact that most NOTCH1 mutated cases were HR and were therefore treated more aggressively. SF3B1 mutations were recorded in 9 cases (11%); no significant associations were found with known biological parameters and, so far, with the ORR and CR rate. A single case harbored a BIRC3 mutation; this patient had an IGHV unmutated status, no FISH abnormalities and a concomitant SF3B1 mutation. In the ML21445 cohort, NOTCH1 mutations were found in 12 cases (15%), were associated with an unmutated IGHV status (p=0.047) and ZAP-70 expression (p=0.007), and did not impact on the ORR and CR rate. SF3B1 mutations were found in 11 cases (13%); no significant associations were found with known biological parameters and the ORR rate. Of interest, only 1/11 SF3B1 mutated patients achieved a CR. BIRC3 mutations were recorded in 3 patients (3.6%); of these, 2 were IGHV mutated, 1 had no cytogenetic abnormalities and 1 carried a del11q, while the third patient was IGHV unmutated status and had no cytogenetic abnormalities. No NOTCH1 and/or SF3B1 mutations were detected. Overall, NOTCH1, SF3B1 and BIRC3 mutations were largely mutually exclusive among each other and with TP53 lesions in the whole cohort. Conclusions: This study confirms the association of NOTCH1 mutations with unfavorable biologic markers and +12, while the presence of SF3B1 mutations was not coupled to poor prognostic markers in CLL patients requiring first-line treatment. Furthermore, it suggests that NOTCH1 mutations impact on the CR rate of young patients receiving Fluda-based regimens, while SF3B1 appears to impact on the CR rate of elderly patients treated with Chlorambucil and Rituximab. Given the small numbers of patients harboring BIRC3, it is at present difficult to draw any conclusion on the clinical impact of this mutation in the cohort of patients hereby analyzed. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.1784.1784
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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